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Updated: Jun 21, 2026

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

Functional antagonism of IL-1alpha induced gene expression profiles define the cAMP/PKA pathway as a unique regulator

David L Murray1, Eric N Johnson, Ping Wang

  • 1Discovery Research and Chemoinformatics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. david.murray@roche.com

Journal of Receptor and Signal Transduction Research
|July 25, 2009
PubMed

Insights

Interleukin-1 (IL-1alpha) triggers inflammation and fibrosis via MAPK/NFkappaB pathways. G(s)-coupled receptor agonists uniquely modulate these IL-1alpha responses, highlighting cAMP/PKA as a key regulatory point.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Pharmacology

Background:

  • Interleukin-1 alpha (IL-1alpha) is a key mediator of inflammatory and pro-fibrotic responses in human lung fibroblasts.
  • These responses are primarily regulated by the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFkappaB) signaling pathways.

Purpose of the Study:

  • To investigate the impact of various compounds, particularly those targeting MAPK and NFkappaB pathways, on IL-1alpha-induced gene expression changes.
  • To identify novel signaling mechanisms that modulate IL-1alpha-mediated responses in lung fibroblasts.

Main Methods:

  • Microarray analysis was employed to establish a reference gene set reflecting IL-1alpha-stimulated cellular responses.
  • The activity of different compounds, including G(s)-coupled receptor agonists, direct pathway inhibitors (p38, JNK, MEK, IKK inhibitors), forskolin, and cAMP analogs, was profiled.
  • Gene expression changes in response to IL-1alpha and compound treatments were analyzed to understand pathway modulation.

Main Results:

  • G(s)-coupled receptor agonists demonstrated a distinct pattern of gene expression modulation in IL-1alpha-stimulated cells.
  • These unique effects were not replicated by direct inhibitors of p38, JNK, MEK, or IKK.
  • Forskolin and cAMP analogs mimicked the effects of G(s)-coupled receptor agonists, suggesting a role for cAMP/PKA signaling.

Conclusions:

  • Cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) act as a convergence point for regulating IL-1alpha responses mediated by various G(s)-coupled receptors.
  • The regulation of IL-1alpha responses by these receptors involves a distinct mechanism that extends beyond the direct inhibition of p38, JNK, MEK, or IKK.
  • Monitoring a small subset of genes can be a sufficient strategy to identify pathway activity for novel compounds, offering a potential paradigm for drug discovery.

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